A particle-based model to investigate nanoparticle diffusion in a 3D biofilm environment

Abstract

<p>Biofilms exhibit heavily increased antibiotic tolerance in comparison to planktonic bacteria, leading to chronic complications during infection. This increased tolerance originates from extracellular polymeric substances (EPS). By binding the antibiotics, they limit access of active compounds to target sites. Embedding the antibiotics in polymer nanoparticles (NPs) provides a promising strategy to deal with this inactivation mechanism. Antibiotic compounds are then protected from unwanted interaction with the biofilm matrix. However, diffusion and subsequently penetration of NPs in the biofilm becomes the limiting factor. Chemical surface modifications would then allow to modify NP interaction with the biofilm and mediate deeper penetration. </p> <p>We present a particle-based model to investigate how structural differences in the biofilm impact NP diffusion, which can later be used to evaluate performance of various NP surface properties. We model the structure of the biofilm, diffusion of low NP concentrations and their interaction with the biofilm. Spherocylindrical bacteria are seeded according to empirically-derived structural parameters such as cell-cell distance, vertical and radial alignment. Interactions with the EPS matrix are represented as spherical zones with higher effective viscosity around the bacteria. We then use this setup to study how differences in biofilm organization and differences in matrix viscosity influence NP penetration depth. </p> <p>We show that sterical interaction with the bacteria alone is insufficient to explain the slowdown in diffusion found in single particle tracking (SPT) experiments. Higher effective EPS viscosity leads to lower NP penetration, but spread of the EPS zones were found to lower NP penetration more. These results are consistent with literature. </p> <p>The method we present here is suitable to evaluate the diffusion and entrapment of NPs in small concentrations in a heterogeneous biofilm environment, taking interactions with EPS and structure of the biofilm into account. Organization of the bacteria and the nature of interaction with EPS can be spatially varied and NPs can actively change the environment. This setup can be used on large scale biofilms, in contrast to computational fluid dynamics approaches, where the amount of computational cells would outscale the number of particles in the simulation. This particle-based model additionally allows to model interactions between NPs such as aggregation. The current coarse graining method for interactions between EPS and NPs allows to increase scale with less strain on the computational cost. This model will provide a solid base to study the fate of nanoparticles in highly heterogeneous biofilms and provide suggestions for NP surface properties and increase success rate for nanomedicine development. </p>